Tirzepatide, a dual GIP/GLP-1 agonist, attenuates endothelial dysfunction and abdominal aortic aneurysm in ApoE-/- mice.

Abdominal aortic aneurysm (AAA) is a life-threatening condition with a high risk of fatal rupture, and current therapeutic options are limited. Endothelial dysfunction is recognized as a critical initiating event in AAA pathogenesis. Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists, like tirzepatide, have shown promise in metabolic diseases and broader cardiovascular benefits. However, the direct impact of tirzepatide on endothelial dysfunction and the development of AAA has remained poorly understood, representing a significant gap in vascular disease research.

Researchers investigated tirzepatide's effects on endothelial dysfunction and AAA using an angiotensin-II (Ang-II)-infused apoE-/- mouse model. In vitro, human endothelial cells were treated with Tirzepatide to evaluate its impact on TNFα-induced leukocyte-endothelium interactions via parallel-plate flow chamber assays. Expression of GLP-1R, GIPR, adhesion molecules (VCAM-1, ICAM-1), and NF-κB activation was quantified using immunofluorescence and western blotting. In vivo, mice received chronic subcutaneous administration of tirzepatide over 28 days to assess its efficacy on suprarenal aortic expansion and AAA incidence.

Both GLP-1R and GIPR were expressed in human endothelial cells and murine suprarenal aortas. Tirzepatide significantly attenuated TNFα-induced leukocyte-endothelium interactions, reducing adhesion molecule expression. Specifically, it downregulated VCAM-1, ICAM-1, and CX3CL1 expression, and inhibited the mRNA expression and generation of MCP-1 and RANTES. Mechanistically, these beneficial effects were driven by the suppression of NF-κB activation. Chronic subcutaneous administration of tirzepatide over 28 days significantly limited suprarenal aortic expansion and reduced AAA incidence in Ang-II-infused mice. This vasoprotective effect was characterized by preserved elastin integrity, reduced neovessel formation, and diminished macrophage accumulation within the aneurysmal wall. > Tirzepatide significantly attenuated TNFα-induced leukocyte-endothelium interactions and reduced AAA incidence in Ang-II-infused mice.